Morita Baylis-Hillman (MBH) reaction a carbon-carbon bond forming reaction between an α,β-unsaturated carbonyl and aldehydes or activated ketones in the presence of a nucleophilic catalyst. The MBH reaction is an atom-economical method of rapid increase of molecular complexity. The development of this process has received considerable attention in recent years. This dissertation presents the development of a new catalytic system for the symmetric and asymmetric MBH reaction. The new system for the racemic version of this reaction was accomplished employing a 1:1:1 ratio of catalytic amounts (10 mol%) of MgI2, TMEDA and DMAP and proved to be highly effective. For the asymmetric version was developed a highly enantio-selective system based on Fu’s planar chiral DMAP derivative (II) with ee´s up to 98%. Abnormal MBH adducts are obtained employing either ethyl 2,3-butadienoate or ethyl propiolate in good yields, in the presence if MgI2 and either a tertiary amine or phosphine as the nucleophile. The α,β-unsaturated carbonyls where prepared by a modified direct α- methylenation using paraformaldehyde, diisopropylammonium trifluoroacetate, and catalytic acid or base with excellent yields for several carbonyls compounds. The Negishi cross-coupling reaction is the Pd or Ni-catalyzed stereoselective cross-coupling or organozincs and aryl-, alkenyl-, or alkynyl halides. Enantioselective Negishi cross-coupling of aryl zincs and α-bromo ketones was accomplished employing a NCN Pincer complex as the catalyst with ee´s up 99%. The required pincer complexes have been prepared by the oxidative addition of pincer ligands with palladium or nickel. Additionally, It has been developed a direct and highly active, (NCN)-Pd catalytic system for the α-arylation of ketones with a variety of aryl bromides using the air and moisture stable [t-BuPheBox-Me2]PdBr (XVI) as the catalyst. The adducts are obtained in excellent yields (92% average for 20 examples) in only 1 hour using 1 mol% of catalyst loading. Perhaps more importantly, the work described here shows that XVI is highly reactive, highly selective, even on substrates bearing challenging functional groups such alkenes.

A brief summary of the use of palladium as a catalyst, the characteristic reactivity of palladium complexes and the commonly used palladium-catalysed cross coupling reactions is given, with a special focus on the palladium-catalysed α-arylation of enolates and its application to the synthesis of aromatic heterocycles. The synthesis of aromatic heterocycles via both traditional methods and more recent metal-catalysed approaches is discussed in the context of isoquinolines. The palladium-catalysed oxidation of dihydrofurans bearing an ortho-bromophenyl group at the 2-position to the corresponding 2-phenyl furans is disclosed along with some preliminary mechanistic investigations. A novel synthetic route to isoquinolines is detailed involving the palladium-catalysed α-arylation of ketone enolates with an appropriate ortho-substituted aryl halide to furnish a protected 1,5-dicarbonyl intermediate. The versatility of these intermediates is demonstrated with their conversion into isoquinolines, isoquinoline N-oxides and naphthols. The scope of the synthetic procedure is fully exemplified across more than 30 different scaffolds covering the full spectrum of electron-rich to electron-deficient moieties. The intermediates were shown to be amenable to functionalisation with electrophiles, leading to isoquinolines bearing additional substitution at the C4 position. Sequential one-pot procedures were developed allowing three and four component couplings to directly deliver highly-substituted isoquinolines from commercially available starting materials. This methodology was utilised in the total synthesis of the natural product berberine in 26% overall yield and a longest linear sequence of six steps.

<strong>Chapter 1. Introduction</strong> Scientific background on the development of homogeneous palladium-catalysed cross coupling reactions, focusing on the &alpha;-arylation reaction of enolates and its application to the synthesis of heteroaromatic compounds. The classical syntheses of isoquinolines are discussed, followed by an account of modern methods for their synthesis, including the recent &alpha;-arylation-based methodology developed by the Donohoe group. <strong>Chapter 2. Results and Discussion</strong> 2.1 Studies towards the development of a palladium-catalysed, C–H activation-based &alpha; arylation reaction of ketones, resulting in a C–H bromination/&alpha;-arylation sequence for the synthesis of isoquinolines and isoquinoline N-oxides. 2.2 The one-pot, four component coupling of a ketone, an acetal protected ortho-bromobenzaldehyde or ketone, an electrophile, and an ammonia source is described. This protocol, which ultimately provides C4 functionalised isoquinolines, is later extended to a novel &alpha;,&alpha; heterodiarylation protocol to furnish C4-aryl isoquinolines. 2.3 It is shown that the synthesis of 3 aminoisoquinolines can be achieved via the &alpha; arylation of nitriles. tert-Butyl cyanoacetate can act as a substitute for primary alkyl nitriles, with sequential &alpha;-arylation, in situ functionalisation, decarboxylation and cyclisation reactions provide C4 functionalised 3 aminoisoquinolines. 2.4 The synthetic utility of the &alpha; arylation based methodology for isoquinoline synthesis is exemplified by the total synthesis of the alkaloid berberine in 68% yield over five steps. This is followed by syntheses of pseudocoptisine, palmatine, dehydrocorydaline, and an unnatural fluorine containing analogue, in yields of 46%, 73%, 60% and 37%, respectively. 2.5 Finally, preliminary investigations demonstrate the utility of palladium-catalysed enolate arylation in the synthesis of &beta;-carbolines.